Carboxymethyl cellulose/quaternized chitosan hydrogel loaded with polydopamine nanoparticles promotes spinal cord injury recovery by anti-ferroptosis and M1/M2 polarization modulation.

Spinal cord injury (SCI) represents a catastrophic neurological condition resulting in long-term loss of motor, autonomic, and sensory functions. Recently, ferroptosis, an iron-regulated form of cell death distinct from apoptosis, has emerged as a potential therapeutic target for SCI. In this study, we developed an injectable hydrogel composed of carboxymethyl cellulose (CMC), and quaternized chitosan (QCS), loaded with modified polydopamine nanoparticles (PDA NPs), referred to as CQP hydrogel. This hydrogel effectively scavenged reactive oxygen species (ROS), prevented the accumulation of Fe2+ and lipid peroxidation associated with ferroptosis, and restored mitochondrial functions in primary neuronal cells. When administered to animal models (rats) with SCI, the CQP hydrogels improved motor function by regulating iron homeostasis, inhibiting ferroptosis, and mitigating oxidative stress injury. Both in vitro and in vivo studies corroborated the capacity of CQP hydrogels to promote the shift from M1 to M2 polarization of microglia/macrophages. These findings suggest that CQP hydrogels, functioning as a localized iron-chelating system, have potential as biomaterials to enhance recovery from SCI by targeting ferroptosis and modulating anti-inflammatory macrophages activity.

Chitosan Hydrogel Dressing Loaded with Adipose Mesenchymal Stem Cell-Derived Exosomes Promotes Skin Full-Thickness Wound Repair.

Cutaneous trauma repair is still a challenge in the clinic due to the scar formation and slow healing rate, especially for diabetic patients. Various drug-loading wound dressings have been explored to solve this problem. Mesenchymal stem cell (MSC)-derived exosomes have been considered as a potential cell-free drug because of their anti-inflammation function and tissue repair property that are comparable to that of MSCs. Herein, a composite wound dressing (Exo/Gel) consisting of the chitosan hydrogel and adipose MSC-derived exosome (ADMSC-Exo) was designed and fabricated by a physical mixing method to promote the skin full-thickness wound repair. The exosomes were slowly released from the Exo/Gel dressing with the degradation of the chitosan hydrogel. The Exo/Gel displayed enhanced cell migration and angiogenic properties in vitro. And the results in the rat skin wound model showed that the Exo/Gel could promote the regular collagen deposition, angiogenesis, and hair follicle mosaicism regeneration. These results proved that the hydrogel dressing with ADMSCs-derived exosomes can accelerate skin wound healing, which is a strategy for developing wound dressings.

The impact of time from injury to surgery on the risk of neuropathic pain after traumatic spinal cord injury.

Traumatic spinal cord injury (SCI) is a devastating neurological disorder often accompanied by neuropathic pain (NeP), significantly affecting patients' quality of life. This retrospective study aimed to investigate the impact of the time from injury to surgery on the development of NeP following traumatic SCI. Medical records of patients with traumatic SCI who underwent surgical intervention between January 2017 and January 2021 at two specialized centers were reviewed. Variables associated with NeP including demographics, injury profiles, medical history, surgical details, and pain assessments were investigated. Independent risk factors related to NeP were identified using multivariate logistic regression analysis. A total of 320 patients met the inclusion criteria, with 245 (76.6%) being male and a mean age of 56.5 ± 13.2 years. NeP was identified in 48.4% of patients (155 of 320). The multivariate analysis identifies age at injury, Injury Severity Score, and the neurological level of injury as independent risk factors for the development of NeP in both AIS A and AIS B, C, and D subgroups. Additionally, a significant association between the time from injury to surgery and NeP was observed in AIS B, C, and D patients, while no such association was found in AIS A patients. This study highlights the benefits of early and ultra-early surgical intervention in preventing NeP in patients with incomplete traumatic SCI (AIS B, C, and D), underscoring the importance of optimizing surgical timing to improve patient outcomes. Prospective studies are warranted to establish evidence-based surgical guidelines for managing traumatic SCI and preventing NeP effectively.

Concomitant malnutrition and frailty are significant risk factors for poor outcome following two-stage revision for chronic periprosthetic joint infection.

BACKGROUND: Two-stage revision remains the gold standard for periprosthetic joint infection (PJI) treatment. Although previous studies have examined malnutrition and frailty independently, their cumulative effects are not clear. Therefore, this study aimed to assess the individual and combined influence of malnutrition and frailty on the two-stage revision surgery. METHODS: Patients with chronic PJI undergoing two-stage revision were retrospectively included. The definition of PJI is completely consistent with the evidence-based definition of PJI recorded by the MSIS in 2018. Preoperative serum albumin levels and 11-item modified frailty index scores were collected. Four cohorts were created: (1) Normal (N), (2) Frail (F), (3) Malnourished (M), and (4) Malnourished and frail (MF). Demographic data, comorbidities, and postoperative complications were collected and compared between the four cohorts. RESULTS: A total of 117 consecutive patients were enrolled, 48% of patients were healthy (27.4% F, 16.2% M, and 9.4% MF). MF group showed lower scores on the physical composite scale of the 12-item short-form health survey (SF12-PCS), mental composite summary (SF12-MCS), Harris hip score (HHS), and knee society score (KSS) (P < 0.05). The incidence of reinfection in the MF group was higher than that in all other groups (MF vs. N; odds ratio [OR] 3.7, 95% confidence interval [CI] 1.37 - 8.82, P = 0.032). The incidence of complications in the MF group was higher than that in all other groups (MF vs. N; OR 4.81, 95% CI 1.58-9.26, P = 0.018). Postoperative transfusion events (OR 2.92, 95% CI 1.27-3.09, P = 0.021), readmission at 60 days after the operation (OR 4.91, 95% CI 1.82-13.80, P = 0.012) was higher in the MF patients. In addition, the extended length of stay after the operation was highest in the MF patients, with an OR of 5.78 (95% CI 2.16-12.04, P = 0.003). CONCLUSION: The concurrent presence of concomitant malnutrition and frailty in patients with PJI is related to poor prognosis and may be a predictor of the efficacy of two-stage revision. Future research will be needed to describe the benefits of improving these risk factors for patients with PJI.

An injectable hydrogel scaffold with IL-1ß-activated MSC-derived exosomes for the treatment of endometritis.

Chronic endometritis is a common gynecological disease resulting from various long-term recurrent infections, and is closely related to myositis, miscarriage, and even infertility. There is still no satisfactory treatment method currently in clinical therapy. Mesenchymal stem cell (MSC)-derived exosomes, an important kind of paracrine product, have been used to treat inflammatory diseases due to their promising immunomodulatory function and tissue repair ability similar to MSCs. Considering that the exosome contents and functions are regulated by the MSC status and the MSC status is significantly influenced by its surrounding microenvironment, we propose a hypothesis that exosomes derived from inflammation-simulated MSCs will possess stronger inhibition ability for inflammation. Herein, we used IL-1ß to activate rat bone MSCs for obtaining ß-exo and constructed an injectable polypeptide hydrogel scaffold by loading ß-exo (ß-exo@pep) for an in situ slow release of ß-exo. The results showed that the polypeptide hydrogel can provide a sustained release of exosomes in 14 days. The ß-exo@pep composite hydrogel can more effectively inhibit the production of inflammatory factors such as TNF-α, IL-1ß, and IFN-γ, while it can promote the production of anti-inflammatory factors such as Arg-1, IL-6, and IL-10. The ß-exo@pep composite hydrogel significantly promoted cell migration, invasion, and vessel tube formation in vitro. The experiments in a rat model of endometritis proved that the ß-exo@pep composite scaffold possessed excellent ability towards anti-inflammation and endometrial regeneration. The research studies on the molecular mechanism revealed that the protein expressions of HMGB1 and phosphorylated IKB-α and p65 are down-regulated in the cells treated with ß-exo@pep, indicating the involvement of the NF-κB signaling pathway. This study provides an effective method for the treatment of chronic endometritis, which is promising for clinical use.

Nebulization of risedronate alleviates airway obstruction and inflammation of chronic obstructive pulmonary diseases via suppressing prenylation-dependent RAS/ERK/NF-κB and RhoA/ROCK1/MLCP signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disorder that causes airway obstruction and lung inflammation. The first-line treatment of COPD is the bronchodilators of ß2-agonists and antimuscarinic drugs, which can help control the airway obstruction, but the long-term use might render the drug tolerance. Bisphosphonates are widely used in osteoclast-mediated bone diseases treatment for decades. For drug repurposing, can delivery of a third generation of nitrogen-containing bisphosphonate, risedronate (RIS) ameliorate the progression of COPD? METHODS: COPD rats or mice models have been established through cigarette-smoking and elastase injection, and then the animals are received RIS treatment via nebulization. Lung deposition of RIS was primarily assessed by high-performance liquid chromatography (HPLC). The respiratory parameters of airway obstruction in COPD rats and mice were documented using plethysmography method and resistance-compliance system. RESULTS: High lung deposition and bioavailability of RIS was monitored with 88.8% of RIS input dose. We found that RIS could rescue the lung function decline of airspace enlargement and mean linear intercept in the COPD lung. RIS could curb the airway obstruction by suppressing 60% of the respiratory resistance and elevating the airway's dynamic compliance, tidal volume and mid-expiratory flow. As an inhibitor of farnesyl diphosphate synthase (FDPS), RIS suppresses FDPS-mediated RAS and RhoA prenylation to obstruct its membrane localization in airway smooth muscle cells (ASMCs), leading to the inhibition of downstream ERK-MLCK and ROCK1-MLCP pathway to cause ASMCs relaxation. Additionally, RIS nebulization impeded pro-inflammatory cell accumulation, particularly macrophages infiltration in alveolar parenchyma. The NF-κB, tumor necrosis factor-alpha, IL-1ß, IL-8, and IL-6 declined in microphages following RIS nebulization. Surprisingly, nebulization of RIS could overcome the tolerance of ß2-agonists in COPD-rats by increasing the expression of ß2 receptors. CONCLUSIONS: Nebulization of RIS could alleviate airway obstruction and lung inflammation in COPD, providing a novel strategy for treating COPD patients, even those with ß2-agonists tolerance.

PD-1 engineered cytomembrane cloaked molybdenum nitride for synergistic photothermal and enhanced immunotherapy of breast cancer.

Incomplete tumor ablation and subsequent tumor metastasis usually occur during photothermal anti-tumor processes. The combination of photothermal and immunotherapy has proven to be a promising method to conquer technical challenges. Inhibiting the programmed death ligand-1 (PD-L1)/programmed cell death protein 1 (PD-1) immune pathway represents one of the most successful immunotherapy strategies. Whereas, the PD-L1 expression level significantly differs, leading to a relatively low response rate to the immune checkpoint blockade (ICB) approaches. Therefore, improving the expression level of PD-L1 becomes one potential method to enhance the response rate. Herein, NIH 3T3 cells were educated to steadily express PD-1 protein. Furthermore, the synthesized molybdenum nitride was then coated with PD-1 protein-modified cytomembrane, which endows it with immune checkpoint blocking capability. Moreover, under the irradiation of near-infrared light, the local mild heat released from the molybdenum nitride causes the apoptosis of tumor cells. More importantly, the elevated temperature simultaneously helps elevate the expression level of PD-L1, further enhancing the response rate of ICB. Finally, the PD-1 cytomembrane coatings interact with the upregulated PD-L1, leading to the activation of the immune system. In summary, we confirmed that the PD-1 protein-coated molybdenum nitride could synergistically ablate tumors and avoid metastasis.